We are currently studying the phenomenon of drug nucleic acid cocrystallization by X-ray crystallography. Several years ago, we successfully cocrystallized actinomycin D with deoxyguanosine and the structure led to an understanding of actinomycin binding to DNA. We have more recently cocrystallized ethidium with two self-complementary dinucleoside monophosphates (5-iodouridylyl(3'-5')adenosine and 5-iodocytidylyl(3'-5')guanosine) and this has allowed the direct visualization of intercalative drug binding to a miniature double-helix. The information obtained from these analyses has led to an understanding of ethidium-DNA binding, and, moreover, has led to unifying structural concepts in understanding a wide range of drug-DNA interactions. Current work deals with 9-aminoacridine, proflavin and acridine orange, all of which form crystalline complexes with self-complementary dinucleoside monophosphates. We have solved a 9-aminocridine: 5-iodocytidylyl(3'-5')guanosine crystalline complex and this structure has revealed an important new feature about drug intercalation in this study. 9-aminoacridine demonstrates a symmetric and an asymmetric binding mode to this miniature Watson-Crick type double helix. The symmetric binding mode may be utilized with DNA intercalation; however, the asymmetric binding mode cannot. We postulate that this second type of interaction is somehow related to the origin of frameshift mutagenesis. BIBLIOGRAPHIC REFERENCES: "Symmetry in nucleic acid structure and its role in protein-nucleic acid interactions", by Henry M. Sobell, Ann. Rev. Biophys. Bioengineering, 5, 307-355 (1976). "Organization of DNA in chromatin", by Henry M. Sobell, Chun-che Tsai, Steven G. Gilbert, Shri C. Jain and T. D. Sakore, Proc. Nat. Acad. Sci. USA 73, 3068-3072 (1976).